Friday, May 10, 2024
5/10/2024
ABSTRACT Preterm infants are at high risk for infections, including those that are vaccine-preventable, for reasons that are incompletely defined. One untested mechanism may involve the high incidence of chorioamnionitis in extremely preterm infants. Chorioamnionitis, a type of antenatal inflammation, is an important cause of preterm birth and is associated with neonatal inflammatory disorders. The links between chorioamnionitis, postnatal infection, and childhood asthma also suggest a negative influence of inflammation on the developing immune program and protective immunity. Th17 cells are adaptive immune cells that contribute to protective immunity but that under inflammatory conditions may limit protective immune responses. We have observed robust Th17-type responses in human preterm infants born after chorioamnionitis and in murine pups delivered after LPS-induced antenatal inflammation. We hypothesize that fetal exposure to inflammation alters developmental immune programming and induces maladaptive postnatal immune responses. This hypothesis could help explain why extremely preterm infants are at particular risk for inadequate protective immunity as well as exaggerated inflammatory responses to infection. In addition, our preliminary data suggest a persistence of elevated Th17 responses in adult mice exposed to antenatal inflammation, which also suggest that immune alterations encountered in fetal life may affect life-long immunity. Our mouse model recapitulates our findings in human infants, and is thus ideal for longitudinal interrogation of this process. In Aim 1 we propose comparative studies in infant and adult murine offspring exposed to antenatal inflammation to characterize inflammatory and protective Th17 responses to vaccination. In Aim 2, we will begin to define the underlying mechanisms by determining the contribution of the microRNAs, miR-155 and miR-146, on Th17-mediated inflammatory and protective immune responses. The results of the proposed studies will enhance our understanding of how fetal inflammatory exposure may impact immunity at different life stages, and will guide subsequent translational and human studies.
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